Design, Synthesis And BK_Ca Channel-opening Activity Of Novel Dehydroabietic Acid Oxime Ether Derivatives

Large-conductance, calcium-activated potassium channels (BK or BKCachannels) belong to calcium activated potassium channels and they are widelyexpressed in various cells and tissues of mammals (except myocardial cells), whichplay important roles in many physiological processes such as intracellular signaltransduction, cellular excitability and metabolic regulation. BKCachannel is apotential drug target for the treatment of coronary heart disease, hypertension,asthma, urinary incontinence, ischemic stroke, etc.Preliminary research showed dehydroabietic acid (DHAA) had weak butdefinite BKCachannel-opening activity. Great deals of efforts have been devoted toscreening DHAA analogs, aiming at obtaining new bioactive compounds withsimpler structures and stronger activities.Starting from dehydroabietic acid, a series of12-oxime ether derivatives weresynthesized via esterification, acylation, oximation, deprotection and other reactionssuccessfully. Based on that, the oxime ether groups were designed and introduced torings B and C to afford some other dehydroabietic acid derivatives.Population Patch Clamp technology is applied to get the BKCachannel-openingproperties of the target compounds. The assay results indicated that the activities ofthe investigated12-oxime ether derivatives were influenced by the arrangement ofthe carboxylic acid functionality of ring Aand the hydrophobic region of ring C.The structures of all the target compounds were confirmed by1H NMR,13CNMR and MS, HR-MS spectra. The melting points of solid compounds weremeasured, and some of the target compounds were analyzed by IR spectroscopy andXRD single-crystal diffraction structure analysis. The structures of the intermediateswere confirmed by1H NMR and13C NMR spectra.